Methylation of lysine and arginine residues on histone tails constitutes important epigenetic marks delineating transcriptionally active and inactive chromatin. For instance, methylation of lysine 9 on histone H3 (H3-K9) is associated with epigenetically silenced chromatin1-3. In contrast to other histone modifications such as acetylation and phosphorylation, methylation has been regarded as irreversible because of the high thermodynamic stability of the N—CH3 bond. Recently however, Shi and coworkers4 identified the protein LSD1, a nuclear amine oxidase homologue, as a histone demethylase highly specific for mono- and di-methylated H3-K4. This enzyme demethylates its substrates through an amine oxidase reaction. However, LSD1 is unable to demethylate tri-methylated lysine H3-K4, most likely due to the absence of a protonated nitrogen required for oxidation4. Just prior to the completion of the present study, Tsukada et al. demonstrated that the Jumonji protein FBXL11 (JHDM1a) can specifically demethylate di-methyl H3-K36 in a Fe(II) and α-ketoglutarate-dependent manner5. Although the reaction mechanism for FBXL11-mediated demethylation at least in theory could utilize tri-methyl H3-K36 as substrate, no such activity could be demonstrated5. Thus, although the identification of LSD1 and FBXL11 as histone demethylases constituted important milestones for epigenetic research demonstrating the dynamic regulation of methyl marks, they have not resolved the question of the reversibility of tri-methylated lysine marks.
As documented by studies of the SUV39H1 knockout mouse, loss of the tri-methyl variant of the H3-K9 mark results in chromosomal aberrations and predisposes to cancer. Hence enzymes capable of reversing this mark have long been sought, although their existence has been questioned. The latter view has been reinforced by the fact that tri-methylated H3-K9 is required for the establishment and maintenance of heterochromatin, a “very stable and heritable chromatin state”. The identification of such enzymes and inhibitors of their activity would provide a novel approach to the prevention and treatment of cancers.